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Introduction: Prostate cancer (PCa) is the second leading cause of cancer deaths among men in the United States. Approximately 50% of patients with PCa harbor an oncogenic TMPRRS2- ERG gene fusion in their primary and 35% of patients with metastatic castration resistant prostate cancer that often coincides with defective PTEN. We have identified a small molecule, ERGi-USU, with previously described metal chelator activity that binds to the atypical kinase RIOK2 and selectively inhibits the growth of ERG positive cancer cells in vitro and in vivo. ERGi- USU is also effective in inhibiting the growth of tumorigenic mouse prostate organoids harboring TMPRSS2-ERG in Pten null background. We developed a salt formulated derivative of ERGi-USU with improved tumor growth inhibition activity. The objective of our study is to gain insights into the mechanism of action of parental and new ERGi-USU compounds. Methods: The anti-tumorigenic activities of ERGi-USU, was assessed in the hormone-refractory metastatic tissue derived ERG positive prostate cancer cell line (VCaP) and mouse prostate derived TMPRSS2-ERG/Pten null organoids. We monitored cell cycle proteins and ferroptosis pathways and RIOK2 in response to treatment with ERGi-USU compounds. The normal primary endothelium derived HUVEC cells were used as normal control due to the normal endogenous expression of ERG in endothelial cells. Results: Cell growth of tumorigenic ERG positive mouse prostate organoids were inhibited in response to ERGi-USU treatments. Consistent with the response of VCaP cells the ERG and RIOK2 protein levels were down regulated by ERGi-USU treatment in ERG positive tumorigenic mouse prostate organoids. Altered levels of ferroptosis associated proteins were found indicating the involvement of ferroptosis in the activity of ERGi-USU compounds. Conclusions: Our results showed that ferroptosis, the iron-dependent form of programmed cell- death may be involved in the cancer selective activity of ERGi-USU compounds. Disclaimer: The contents of this publication are the sole responsibility of the author(s) and do not necessarily reflect the views, opinions or policies of Uniformed Services University of the Health Sciences (USUHS), The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., the Department of Defense (DoD), the Departments of the Army, Navy, or Air Force. Mention of trade names, commercial products, or organizations does not imply endorsement by the U.S. Government. Citation Format: Binil Eldhose, Katherine Beck, Cyrus Eghtedari, Gartrell C. Bowling, Mallesh Pandrala, Sanjay V. Malhotra, Xiaofeng A. Su, Albert Dobi. ERGi-USU selectively inhibit ERG positive prostate cancer through ATF3 mediated ferroptosis [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr B062.